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TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.

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All the data of this study are provided in the paper and Supplementary Information. Other information on the data is available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank S. Porta and V. Lee (University of Pennsylvania) for mouse-specific TDP-43 antibodies; M. Tada and A. Kakita (Niigata University) for their thoughtful comments on human pathology; S. Shibata (Niigata University) for suggestions in electron microscopic analyses; Y. Yoshida (Burke Neurological Institute) for approving use of mouse lines; K. Hoshina (Niigata University) and other lab members for their technical assistance; T. Yamashita (Osaka University) and K. Shibuki (Niigata University) for supporting materials. This work was supported by Tsubaki Neurology grant and JSPS KAKENHI (22K15637) (S.T.); AMED-CREST (JP19gm1210005), Moonshot Research (J21zf0127004), JSPS KAKENHI (21H02590B), ALS Foundation (Japan ALS Association) (M.U.); JSPS KAKENHI (19H01043) (O.O.).

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  1. Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, 951-8585, Japan

    Shintaro Tsuboguchi, Tomohiko Ishihara, Hideki Mori, Yuka Koike & Osamu Onodera

  2. Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Japan

    Yuka Nakamura, Tokiharu Sato & Masaki Ueno

  3. Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata, Japan

    Taisuke Kato & Osamu Onodera

  4. Division of Legal Medicine, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan

    Akihide Koyama

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  1. Shintaro Tsuboguchi
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Supplementary file2 Supplementary Movie 1. Severe forelimb paralysis at 8 weeks after AAV-CAG-DIO-Myc-mtTDP-43 injection in the spinal cord of Chat-Cre mice. (MOV 14317 kb)

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Tsuboguchi, S., Nakamura, Y., Ishihara, T. et al. TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models. Acta Neuropathol 146, 611–629 (2023). https://doi.org/10.1007/s00401-023-02615-8

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